Human infertility is a global problem and failure of embryo implantation accounts for a significant percentage of pregnancy failure during both natural pregnancy and in vitro fertilization procedures. Implantation is an extremely complicated process requiring precisely controlled hormonal, growth factor signaling and cell-cell contacts which coordinate interactions between the competent blastocysts and the receptive uterus. Decidualization is part of the implantation process and involves rapid proliferation then differentiation of fibroblast-like endometrial stromal cells into epitheloid-like decidual cells whch later become part of the decidual tissue that surrounds the implanting conceptus. Decidualization defects can directly lead to implantation failure. In addition, early decidualizatin defects can also lead to other pregnancy defects such as placentation, intrauterine fetal growth, and parturition. Up to now, the process of decidualization has not been systematically studied due to the lack of a suitable high throughput screening tool. Here we describe the generation of such an in vitro screening tool that contains a fluorescent readout for decidualization. In Aim I we will use this in vitro screening tool to perform a genome-wide shRNA screen to identify novel genes for decidualization. In Aim II, we will analyze the temporal induction of transcription factors required for decidualization and establish a transcription factor network leading to decidualization. Successful completion of this project will have a long-lasting impact in multiple research fields including implantation biology, contraception, in vitro fertilization and environmental toxicology.